The present invention relates to an improved process for the preparation of .alpha.-aryl propionic acids by the photochemical reaction of haloalkyl aryl ketones. .alpha.-aryl propionic acids are useful as anti-inflamatory, anti-pyretic and analgesic agents.
The preparation of .alpha.-aryl propionic acids has so far followed the so-called classic chemical methods which employ as starting material aryl alkyl ketone derivatives and are known by such names as Darzen's reaction, Willgerodt's reaction, Arndt-Eistert's reaction and Friedel-Crafts reaction. Of these, Darzen's reaction constitutes more or less the generally accepted basic method for the preparation of .alpha.-aryl propionic acids. This method comprises the reaction of aryl alkyl ketones with alkyl chloroacetate in the presence of alkali metal alkoxides in an alcoholic solvent. [D. R. White (The Upjohn Company) U.S. Pat. No. 3,975,431 (1976); Chemical Abstracts 86,5168 w].
An alternative method for the preparation of .alpha.-aryl propionic acids involves the alkaline hydrolysis of .alpha.-aryl propionitrile or its derivatives [N. Tokutake (Shionogi and Company Limited), Japanese Pat. No. 77,111,536 (1977); Chemical Abstracts 88: 50512f].
Other prior art methods include the chemical re-arrangement of .alpha.-haloalkyl aryl ketones in the presence of Lewis acids [Claudio Giordao, Graziano Castaldi & Fulvio Uggeri, Agnewandte Chemie, International Edition, English, 23 (1984) 413-419 ]; the .alpha.-alkylation of aryl acetic esters or aryl acetonitriles [W. G. Kenyon, R. B. Meyer and C. R. Hauser, Journal of Organic Chemistry, 28(11), 3108 (1963)]; and "Research on biphenyl, stilbene and diphenylethane derivatives" [G. Cavallini, E. Massarani, D. Nardi and R. D'Ambrosio, Journal of the American Chemical Society, 79, 3514 (1957)].
More recently, newer methods have been proposed for the preparation of .alpha.-aryl propionic acids. These include Gassman's procedure and vicarious neucleophilic substitution and chemical re-arrangement of propionic acid derivatives [P.G. Gassman and T. J. Van Bergen, Journal of the Americal Chemicals Society, 96(17), 5508 (1974); G. P. Stahly, B. C. Stahly and K. C. Lilge, Journal of Organic Chemistry, 49 579 (1984); M. S. Newman and B. J. Magertein, Organic Reactants V, 413 (1949); Brown, E. V. Synthesis, 358 (1975); S. Yoshimura, S. Takahashi and M. Ichino (Kohjin Company), Japanese Pat. No. 76,36,432 (Mar. 27, 1976); and Chemical Abstract 85,123596 m].
While the prior art processes suffer from a few minor drawbacks, there is one major disadvantage which is common to all of them and that is the multiplicity of reactions and the overall length of time taken. In almost every instance, a number of reaction steps involving lengthy sequences of introduction of reactants are involved. Such reactants include alkyl or carboxylic ester groups with suitable precursors. Frequently, such steps take from 12 to 24 hours and the overall time for recovery of the final product is even longer.
The lesser drawbacks of the prior art processes include the employment of toxic reactants such as sodium cyanide, the use of relatively expensive materials such as isopropyl monochloroacetates and the difficulty of reproducing the reactions for a large scale operation without leading to the formation of a number of undesirable by-products.
The principal object of the present invention is to provide a process for the preparation of .alpha.-aryl propionic acids which does away with the essential drawback of multiplicity of steps and overall length of time of the reaction endemic in the prior art.
A more specific object resides in the provision of a one-step process for the preparation of .alpha.-aryl propionic acids employing easily obtainable starting products and which avoids the use of expensive or hazardous raw materials for the reaction.
Towards achieving their objective, the applicants have researched the area of photochemistry and have been able to establish that it is possible to obtain the desired .alpha.-aryl propionic acids in a single step treatment by subjecting a haloalkyl aryl ketone to irradiation with light of a particular wavelength.
Accordingly, the present invention provides a process for the photochemical production of .alpha.-aryl propionic acids of the general formula: ##STR1## wherein X is a radical of the structure: ##STR2## wherein R is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-amyl, isoamyl, chloro, methoxy or phenyl and R.sup.1 is hydrogen or halogen which comprises subjecting an -haloaryl alkyl ketone of the general formula: ##STR3## wherein X has the meanings stated above to irradiation with light having a wavelength of from 200 to 800 nm in the presence of an anhydrous or aqueous organic solvent at a temperature from 0.degree. C. to the boiling point of the solvent.
The light employed for irradiation can be either sunlight or artificial light, for instance the light of a mercury vapour lamp.
Effectively, the reaction is carried out over a period of from 1.5 to 20 hours.
In accordance with a preferred feature of the invention, esters of .alpha.-aryl propionic acids formed during the photocohemical reaction are hydrolysed in situ by means of aqueous alkali to provide the corresponding acids.
Examples of the ketones that may be employed as starting materials in the process of the present invention include .alpha.-chloropropionphenone, .alpha.-chloro-1-(4'-chlorophenyl)-1-propanone, .alpha.-chloro-1-(4'-methylphenyl)-propanone, .alpha.-chloro-1-(4'-isobutylphenyl)-1-propanone, .alpha.-chloro-1-(4'-methoxyphenyl)-1-propanone and 2-chloro-1-(4'-methoxyphenyl)-1-propanone.
A particularly preferred ketone is (6-methoxy-2-naphthyl)-.alpha.-chloroethyl ketone of the formula: ##STR4##
Subjection of this ketone to irradiation of the intensity described above in the presence of the stated solvents converts it to the corresponding .alpha.-(6-methoxy-2-naphyhyl)-propionic acid of the formula: ##STR5## Preferred solvents for the reaction include acetone, methyl alcohol, ethyl alcohol, acetonitrile and tetrahydrofuran.
The reaction according to the invention for the conversion under the influence of light irradiation of .alpha.-halo aryl alkyl ketones to .alpha.-aryl propionic acids generates simultaneously equimolar amounts of hydrohalogen acid such as hydrochloric acid. It therefore becomes necessary to neutralise the hydrohalogen acid produced.
According to a further feature of the invention, therefore, a suitable acid scavenger is incorporated into the solution of solvent and .alpha.-aryl alkyl ketone prior to irradiation thereof. Since the reaction liberates hydrohalogen acid in molar proportions, it becomes necessary to employ the scavengers in equivalent amounts.
Examples of suitable acid scavengers that can be employed with the process of the present invention include potassium carbonate, epichlorohydrin, triethylamine and propylene oxide.
The invention will now be illustrated in greater detail in the following examples.